Huntington's Disease (“HD”) is a fatal autosomal dominant neurodegenerative disorder characterized by age dependent progressive neurological dysfunction and selective loss of neurons in the striatum and cortex. The genetic cause of HD is an abnormal expansion of CAG repeats (>40 repeats) encoding polyglutamine (polyQ) in exon 1 of the huntingtin gene (Htt). Although the genetic cause of HD has been identified, the pathogenic mechanisms of the disease remain unclear, and no therapy that ameliorates the neurodegenerative process is available.
Mitochondrial dysfunction has been highlighted as a critical driver of HD pathophysiology3-5. Mitochondria are important in diverse cellular functions, including bioenergetics, calcium homeostasis and apoptotic signaling. Several proteolytically cleaved N-terminal fragments of mutant Htt proteins have been identified in cells and appear to be more cytotoxic and prone to aggregation than full-length mutant Htt6-8. Ultrastructural and biochemical evidence indicates that N-terminal fragments of mutant Htt associate with mitochondria in cellular and animal models of HD9-11. However, the mechanism directly linking mutant Htt and mitochondrial dysfunction remains unknown.
Mitochondria contain approximately 1,500 different proteins, 99% of which are encoded by the nuclear genome12. Therefore, the import, sorting and assembly of nuclearly encoded mitochondrial proteins are essential for normal mitochondrial function. Only 13 proteins of the respiratory chain are encoded by the mitochondrial genome and synthesized in mitochondria. Nuclearly encoded mitochondrial proteins are synthesized in cytosolic ribosomes as precursor proteins and imported into mitochondria by evolutionarily conserved multi-subunit mitochondrial membrane translocases: translocase of the outer membrane (TOM) and translocase of the inner membrane (TIM)12,13. Whereas the TOM complex serves as the entry gate for almost all nuclearly encoded proteins, two distinct TIM complexes, the TIM23 and TIM22 complexes, act in the inner membrane. The TIM23 complex imports all matrix proteins and a subset of inner membrane and intermembrane space proteins, which harbor N-terminal cleavable presequences. The TIM22 complex, a carrier translocase, imports hydrophobic inner membrane proteins through internal targeting signals. Thus, nuclearly encoded mitochondrial proteins use specific import systems for precise mitochondrial localization. Blockade of import pathways is believed to lead to mitochondrial dysfunction14.